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Gene Expression-Based Dose Response Analysis of Short-Term Rat and Fathead Minnow Exposures to Two Metal Sulfates Indicates Chronic Chemical Potency
Citation:
Wehmas, L., K. Flynn, M. Hazemi, S. Hester, AND Dan Villeneuve. Gene Expression-Based Dose Response Analysis of Short-Term Rat and Fathead Minnow Exposures to Two Metal Sulfates Indicates Chronic Chemical Potency. SETAC, Louisville, KY, November 12 - 16, 2023. https://doi.org/10.23645/epacomptox.24794595
Impact/Purpose:
Chemical risk assessments can take the US EPA years to complete; however, during this time chemical exposures to people and wildlife continue with uncertain health and environmental impacts. Dose response modeling of changes in gene expression from shortterm (days to weeks) chemical exposures can measure potency which is similar that from longterm studies that are used in traditional chemical risk assessment. This has mostly been shown in 2-year mouse and rat studies and less so in wildlife like fish. Similarities at the gene-level between rats and fish suggest there could be some consistency in gene response which could translate to chemical potency measures. Therefore, use of this approach could shorten the time, limit the costs, and reduce the number of longterm animal studies needed for chemical risk assessments at EPA. The present study measured gene response in whole fathead minnow larvae and National Toxicology Progam archived rat liver and lung tissue following 1- or 15-day exposures, respectively, to cupric (CuSO4) and nickel sulfate (NiSO4). The fathead minnows were exposed to 9 concentrations plus control (n=8) of CuSO4 (0.00005 to 0.2 mg/L) or NiSO4 (0.00016 to 1.58 mg/L) by water whereas adult rats (male and female) were exposed to 4 dose-levels plus control (n=5/sex) of CuSO4 by diet (90-770 mg/kg) or NiSO4 by air (3.5-15 mg/m3). Benchmark concentration analysis of fathead minnow genes suggested CuSO4 was more potent than NiSO4 at 0.0021 and 0.053 mg/L, by total metal respectively. This was close to the longterm no observed effect concentrations for total copper and nickel of 0.0093 and 0.11 mg/L, respectively. The gene expression based benchmark dose for rats were 158 mg/kg for CuSO4 and 0.91 mg/m3 for NiSO4, which were slightly less sensitive, but within 10-fold, of the lowest, 2-year benchmark dose-levels of 33 mg/kg for CuSO4 (stomach hyperplasia) and 0.11 mg/m3 for NiSO4 (tooth malformation). These case studies suggest gene response from shortterm chemical exposures can provide reasonable estimates of longterm chemical potency in both fish and rats, which can help EPA perform more efficient chemical risk assessments. The views in this abstract do not represent the US EPA.
Description:
Benchmark dose modeling of gene response from short-term chemical exposures can identify points of departure consistent with chronic adverse effects. Widespread use of this approach could enhance the efficiency of human and ecological risk assessments. Moreover, an understanding of species-specific differences in gene response could aid in risk translation of chemicals. The present effort measured gene response in whole fathead minnow larvae and archival rat liver and lung tissue following 1- or 15-day exposures, respectively, to cupric (CuSO4) and nickel sulfate (NiSO4). The fathead minnows were exposed to 9 concentrations plus control (n=8) of CuSO4 (0.00005 to 0.2 mg/L) or NiSO4 (0.00016 to 1.58 mg/L) in water whereas adult rats (male and female) were exposed to 4 dose-levels plus control (n=5/sex) of CuSO4 by ingestion (90-770 mg/kg) or NiSO4 by inhalation (3.5-15 mg/m3). For the rat studies, tissue type was selected based on the National Toxicology Program pathology reports. Gene expression was measured by RNA-sequencing followed by benchmark dose/concentration (BMD/C) analysis in BMDExpress2. Individual dose/concentration responsive genes were then mapped to gene-sets (e.g., associated with pathways or functional annotations) with the median of the most sensitive defining the BMD/C for comparison with traditional, chronic measures of toxicity. BMC analysis of fathead minnow genes revealed CuSO4 was more potent than NiSO4 with values at 0.0021 and 0.053 mg/L, by total metal respectively. This corresponded with the chronic no observed effect concentrations for total copper and nickel of 0.0093 and 0.11 mg/L, respectively. The gene-set based BMDs for rat was 158 mg/kg for CuSO4 and 0.91 mg/m3 for NiSO4. These values were also consistent, if slightly less sensitive than the most sensitive 2-year BMD values of 33 mg/kg for CuSO4 (stomach hyperplasia) and 0.11 mg/m3 for NiSO4 (tooth malformation). These results suggest utility in using gene response to estimate chronic chemical potency. The views in this abstract do not represent the US EPA.
URLs/Downloads:
DOI: Gene Expression-Based Dose Response Analysis of Short-Term Rat and Fathead Minnow Exposures to Two Metal Sulfates Indicates Chronic Chemical Potency
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